Nitrooxymethyl‐Substituted Analogues of Celecoxib: Synthesis and Pharmacological Characterization

Abstract

Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.Introduction. -Cyclooxygenase (COX) is one of the key enzymes implicated in the transformation of arachidonic acid into prostanoids. It exists in at least two isoforms, COX-1 and COX-2. The former is prevalently a constitutive and the latter an inducible isoform. Selective blocking of these isoforms induces specific pharmacological effects which can be exploited in therapy [1]. COX-2-Selective inhibitors (Coxibs) are a new class of drugs recently introduced into the market [2]; they induce anti-inflammatory effects without the gastrotoxic side-effects typical of the classical non-steroidal antiinflammatory drugs (NSAIDs), which are nonselective COX inhibitors. An interesting aspect of these drugs is their potential use in treating Alzheimers disease and certain forms of cancer [3] [4]. The drawback in their use is that they increase the risk of heart attack and stroke [5] [6]. Blood vessels and platelets are the major targets of prostanoids such as prostacycline PGI 2 , prostaglandin PGE 2 , and thromboxane TxA 2 in the cardiovascular system. The proaggregatory and vasoconstrictor TxA 2 is mainly synthesized via COX-1 in the platelets, while vasodilator (PGI 2 , PGE 2 ) and antiplatelet (PGI 2 ) compounds are synthesized mainly in the vascular endothelium. A strategy to improve the benefit -risk profiles of these drugs is to design a multi-target drug by combining COX-2-selective inhibition with nitric oxide (NO)-dependent activities. NO displays a variety of effects in the cardiovascular system, including vasodilation, inhibition of platelet aggregation, modulation of platelet and leukocytes adherence to vessels, and inhibition of smooth muscle cell proliferation [7]. Examples of this type of approach have already been reported [8] [9] including by our group [10] [11]. As a development of our work in this field, we now describe the synthesis and structural characterization of a new series of NO-donor COX-2 inhibitors obtained by introducing NO-donor nitrooxy functions into the well-known selective COX-2

Nitrooxymethyl‐Substituted Analogues of Rofecoxib: Synthesis and Pharmacological Characterization

“…By contrast, its dihydroxy analog 14 is a quite potent and selective COX-1 inhibitor. The COX inhibitory profiles of the nitrooxy-substituted Rofecoxib compounds and of their OH analogs here described parallel very well those of the related Celecoxib derivatives previously described [26]. The only difference is the definitively lower inhibitor activities of the bis(hydroxymethyl)-and bis(nitrooxymethyl)-substituted compounds 14 and 15, respectively.…”

Nitrooxyacyl Derivatives of Salicylic Acid: Aspirin‐Like Molecules that Covalently Inactivate Cyclooxygenase‐1

“…After incubation, HEK cells were stimulated with 60 μ M arachidonic acid for 15 min at 37 °C 18. Levels of PGE 2 in the supernatant were determined by EIA 28…”

Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach

“…In 2009 and 2010, other research groups tried to obtain a better COX-2/NO donor hybrid. Although none of the compounds demonstrated better anti-inflammatory activity than celecoxib, they showed fewer adverse effects [64,65]. The data indicated that product 57 , obtained by Boschi and coworkers, and derived from substituting the nitrooxymethyl function for the methyl group of celecoxib (IC 50 = 1.3 ± 0.4 μM), was a weak COX-2 inhibitor, being ca.…”

“…The data indicated that product 57 , obtained by Boschi and coworkers, and derived from substituting the nitrooxymethyl function for the methyl group of celecoxib (IC 50 = 1.3 ± 0.4 μM), was a weak COX-2 inhibitor, being ca. 50 times less potent than the lead drug, but it retained a good degree of COX-2 selectivity (IC 50 = 67 ± 19 μM): it also displayed negligible COX-1 activity when tested at 100 μM concentration (Figure 31) [64]. …”